EP2397152B1 - Use of cardiotrophin- 1 for the treatment of metabolic diseases - Google Patents

Use of cardiotrophin- 1 for the treatment of metabolic diseases Download PDF

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EP2397152B1
EP2397152B1 EP10710061.2A EP10710061A EP2397152B1 EP 2397152 B1 EP2397152 B1 EP 2397152B1 EP 10710061 A EP10710061 A EP 10710061A EP 2397152 B1 EP2397152 B1 EP 2397152B1
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insulin
sequence
cardiotrophin
treatment
identity
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English (en)
French (fr)
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EP2397152A2 (en
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Jesús María PRIETO VALTUEÑA
Matilde Bustos De Abajo
María Jesús MORENO ALIAGA
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Proyecto de Biomedicina CIMA SL
Universidad de Navarra
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Proyecto de Biomedicina CIMA SL
Universidad de Navarra
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/204—IL-6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention is related to the use of cardiotrophin-1 (CT-1) for the treatment of obesity and associated disorders: hyperglycaemias, insulin resistance, development of type 2 diabetes and dyslipemias and given its anorexigenic role, fat oxidation stimulant, hypoglycaemic, sensitizing agent of the action of insulin on a skeletal muscle level and inhibitor of the intestinal transport of glucose by enterocytes.
  • CT-1 cardiotrophin-1
  • Obesity is a serious public-health problem which has reached epidemic proportions in many developed countries ( Bellanger and Bray, 2005, J The State Med Soc;157:S42-49 ; quiz 49).
  • the increased food intake, unhealthy diet habits, and sedentary lifestyle in our developed countries have undoubtedly contributed to the obesity boom ( Stein and Colditz et al., 2004, J. Clin. Endocrinol. Metab. 89:2522-5 ).
  • Many studies have shown that the alarming increase in the prevalence of obesity and its metabolic disorders is associated to insulin resistance, dyslipemias, and eventual failure of the beta cells in the pancreas, leading inexorably to type 2 diabetes with all the consequences this disease entails ( Rana et al., 2007, Diabetes Obes. Metab., 9:218-232 ).
  • Xenical is an inhibitor of gastrointestinal lipase which produces a moderate weight loss but has the main problem of adverse gastrointestinal effects, including colon cancer.
  • Sibutramine is a monoamine-capturing inhibitor which produces a greater weight loss than the previous treatment, but is associated to an increase in blood pressure and an increase in cardiac output.
  • Rimonabant which is approved in Europe (though not by the FDA), and is an endocannabinoid receptor antagonist, but which has the problem of causing alterations in emotional behaviour such as depression, for which reason it has been withdrawn from the market.
  • thiazolidinediones are used in combination with other therapies.
  • the problem with these drugs is weight gain, especially when administered together with insulin. From all of this it can be gathered that an agent capable of sensitizing or increasing insulin action in addition to reducing body weight may be of great interest in these pathologies.
  • treatments with peripheral actions such as intestinal glucose inhibition could be of great interest in obesity and diabetes mellitus.
  • leptin at the end of 1994 opened up new horizons in the study of the factors secreted by the adipocyte in regulating energy balance.
  • This protein is mainly produced and secreted by the adipocyte proportionally to the fat mass.
  • This protein was identified as a central nervous system modulator for appetite regulation, in addition to peripheral actions increasing fat oxidation and glucose capture by muscles.
  • obesity was related to high leptin levels and that endogenous leptin was not effective, for which reason the majority of obese humans and rodents were leptin-resistant, therefore this therapeutic weapon would be limited to individuals with disorders that result in leptin deficiency (a low percentage of obese people).
  • leptin is structurally similar to the cytokines of the gp-130 family and the leptin receptor (LRb) is structurally similar to the gp130 cytokine receptor known as gp-130Rbeta
  • LRb leptin receptor
  • CNTF gp-130Rbeta
  • the CNTF cytokine has a possible therapeutic potential in mice suffering from obesity, insulin resistance, and a fatty liver, as it improves all these parameters ( Sleeman et al., 2003, Proc Natl Acad. Sci. USA, 100:14297-14302 ).
  • the anorexigenic role of CNTF (Stephens TW et al., 1995), the capacity of this cytokine to revert insulin resistance through the AMPK activation capacity ( Watt et al., 2006, Nat.
  • the invention is related to a compound that induces cardiotrophin 1 (CT-1) activity for the treatment of a metabolic disease, as well as to the use of a compound that induces cardiotrophin 1 (CT-1) activity for the preparation of a drug for the treatment of a metabolic disease according to the claims.
  • CT-1 cardiotrophin 1
  • the invention is related to cosmetic methods which comprise administering the patient a pharmaceutically active quantity of a compound that induces cardiotrophin 1 activity according to the claims.
  • the invention is related to a composition that comprises, together or separately, a compound that induces cardiotrophin activity and an anti-diabetic compound.
  • the invention is related to a composition in accordance with the invention for the treatment of a metabolic disease, wherein the composition is administered simultaneously, separately or sequentially, as well as to the use of a composition in accordance with the invention for the preparation of a drug for the treatment of a metabolic disease, wherein the composition is administered simultaneously, separately or sequentially.
  • the invention is related to cosmetics methods that comprise administering the patient a pharmaceutically active quantity of a composition in accordance with the invention.
  • CT-1 is capable of causing weight reduction in mice fed a normal diet as well as in mice fed a high-fat diet. Said effect depends, at least in part, on the anorexigenic effect of CT-1 ( figure 2 ) as well as on the capacity of CT-1 of decreasing the increase in plasma lipids following a high-fat diet ( figures 20 and 21 ), of decreasing blood sugar after a high sugar diet ( figures 5-6 ), of causing an increase in glucose consumption by muscles ( figure 8 ) and of decreasing glucose capture by the intestine ( figures 11-14 ).
  • CT-1 is able to inhibit basal and insulin-stimulated leptin secretion in adipocytes, as well as to induce the release of glycerol and the inhibition of the anti-lipolytic activity of insulin ( figures 16 and 17 ).
  • these effects are not observed when CNTF is used. While not adhering to any particular theory, it is thought that this differential effect might give the use of CT-1 an advantage, since said effect would be added to the action that this molecule has on muscle (stimulation of glucose capture with the consequent hypoglycaemia), causing a decrease in the glucose available for the adipocyte to turn into triglycerides.
  • the invention is related to a compound that induces cardiotrophin 1 (CT-1) activity for the treatment of a metabolic disease. Additionally, the invention is related to the use of a compound that induces cardiotrophin-1 activity for the preparation of a drug for the treatment of a metabolic disease as well as with a method of treatment of a metabolic disease which comprises administration to a subject of a compound that induces CT-1 activity.
  • CT-1 cardiotrophin 1
  • the term "compound that induces cardiotrophin-1 activity”, as used here, is understood as any compound administration of which causes an increase in cardiotrophin-1 activity (CT-1) irrespective of whether said increase is caused by an increase in the specific activity of the pre-existing CT-1 or by an increase in the synthesis of CT-1 or analogs thereof that substantially share the same function as cardiotrophin.
  • CT-1 cardiotrophin-1 activity
  • the agent that induces CT-1 activity is CT-1 itself.
  • CT-1 is understood as the protein defined by the sequence described in the UniProtKB database by access number CTF1_HUMAN or Q16619 in version 62 dated 16-DEC-2008, corresponding to isoform 1 of human cardiotrophin, or access number Q5U5Y7 in its version 1 dated 20.01.2009, corresponding to isoform 2 of human cardiotrophin, as well as orthologues in other species, such as mouse (sequences defined in the UniProtKB database with access numbers NP_031821 or Q60753 in version 50 dated 16.12.2008, and NP_942155 or P83714 in version 42 dated 16.12.2008), rat (sequences defined in the UniProtKB database with access numbers NP_058825 or Q63086 in version 50 dated 04.11.2008, and NP_001129272 or Q6R2R3 in version 30 dated 20.01.2009) and chimpanzee (sequence defined in the UniProtKB database with access number NP_00100
  • the agent that induces CT-1 activity is a functionally equivalent variant of CT-1.
  • the expression "functionally equivalent variant of CT-1", as used here, is understood as any molecule which shares with CT-1 one or more of the functions described in the present invention associated to CT-1, both in vitro and in vivo and which has a minimum of 90% identity in the amino acid sequence.
  • variants of CT-1 suitable for their use in the present invention are derived from the aforementioned sequences by insertion, substitution or deletion of one or more amino acids and include natural alleles, variants resulting from alternative processing and secreted and truncated forms which appear naturally.
  • the variants of CT-1 show an identity of sequence with CT-1 of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.
  • the degree of identity is determined using methods very well known to those skilled in the art.
  • the identity between two amino acid sequences is preferably determined using the BLASTP algorithm [ BLASTManual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md. 20894 , Altschul, S., et al., J. Mol. Biol. 215: 403-410 (1990 )] preferably using the default parameters.
  • the variants of CT-1 envisaged show at least one of the functions of CT-1 such as, without limitation:
  • the agent capable of inducing CT-1 activity is a polynucleotide that codes for CT-1 or a functionally equivalent variant thereof.
  • polynucleotide as used in the present invention, relates to a polymeric form of nucleotides of any length and formed by ribonucleotides and/or deoxyribonucleotides.
  • the term includes both single-chain and double-chain polynucleotides, as well as modified polynucleotides (methylated, protected and such like).
  • Polynucleotides suitable for use as agents capable of inducing CT-1 activity include, without limitation, the polynucleotides the sequences of which correspond to those described in the GenEMBL database with access numbers BC064416 in version 9 with date 15.10.2008, corresponding to variant 1 of the transcript of human cardiotrophin, BC036787 in version 9 with date 12.08.2009, corresponding to variant 1 of the transcript of human cardiotrophin, the sequence described in the GenEMBL database with access number D78591, in its version 4 of 12.01.2009, corresponding to the polynucleotide that codes for cardiotrophin 1 of Rattus norvegicus (rat), the sequence described in the GenEMBL database with access number AY518205, in its version 3 of 12.01.2009, corresponding to the polynucleotide that codes for cardiotrophin 2 of Rattus norvegicus (rat), the sequence described in the GenEMBL database with access number U18366, in its version 4 of 12.01.2009, corresponding to the polynucleotide that
  • the agents capable of inducing CT-1 activity include functionally equivalent variants of the polynucleotides previously defined by means of their specific sequences.
  • “Functionally equivalent polynucleotide” is understood, in the context of the present invention, as all those polynucleotides capable of coding for a polypeptide with CT-1 activity, as previously defined, and which result from the aforementioned polynucleotides by means of the insertion, deletion or substitution of one or several nucleotides with respect to the aforementioned sequences.
  • the variant polynucleotides of the present invention are polynucleotides the sequence of which allows them to hybridize in highly restrictive conditions with the aforementioned polynucleotides.
  • Typical conditions of highly restrictive hybridization include incubation in 6 X SSC (1 X SSC: 0.15 M NaCl, 0.015 M sodium citrate) and 40% formamide at 42 °C for 141 hours, followed by one or several cycles of washing using 0.5 X SSC, 0.1% SDS at 60°C.
  • highly restrictive conditions include those which comprise hybridization at an approximate temperature of 50°-55° C in 6X SSC and a washing final at a temperature of 68° C in 1-3 X SSC.
  • the moderate restrictive conditions comprise hybridization at a temperature of approximately 50° C until 65° C in 0.2 or 0.3 M NaCl, followed by washing at approximately 50° C until 55° C in 0.2X SSC, 0.1% SDS (sodium dodecyl sulfate).
  • the agent capable of inducing CT-1 activity is a polynucleotide
  • this is operationally associated to a regulatory region of the expression.
  • the regulatory sequences used in the present invention can be nuclear promoter sequences or, alternatively, enhancer sequences and/or other regulatory sequences that increase the expression of the heterologous nucleic acid sequence.
  • the promoter can be constitutive or inducible. If one wants a constant expression of the heterologous nucleic acid sequence, then a constitutive promoter is used. Examples of well-known constitutive promoters include the cytomegalovirus (CMV) immediate-early promoter, Rous sarcoma virus promoter and such like.
  • CMV cytomegalovirus
  • constitutive promoters are well known in the state of the art and can be used in the practice of the invention. If the controlled expression of the heterologous nucleic acid sequence is desired, then an inducible promoter should be used. In a non-induced state, the inducible promoter is "silent". "Silent" means that in the absence of an inducer little or no expression of the heterologous nucleic acid sequence is detected; in the presence of an inducer, however, the expression occurs of the heterologous nucleic acid sequence. Frequently, it is possible to control the expression level by varying the inducer concentration.
  • Controlling the expression for example varying the concentration of the inducer so that an inducible promoter is more strongly or more weakly stimulated, it is possible to affect the concentration of the transcript product of the heterologous nucleic acid sequence.
  • the heterologous nucleic acid sequence codes for a gene, it is possible to control the quantity of synthesized protein. In this way, it is possible to vary the concentration of the therapeutic product.
  • inducible promoters are: an estrogen or androgen promoter, a metallothionein promoter, or a promoter that responds to ecdysone. Many other examples are well known in the state of the art and can be used in the practice of the invention.
  • tissue promoters can be used to achieve expression of the heterologous sequence of specific nucleic acid in cells or tissues.
  • specific tissue promoters include different specific muscle promoters including: skeletal ⁇ -actin promoter, cardiac actin promoter, skeletal troponin C promoter, cardiac troponin C promoter and of slow contraction, and the creatine kinase promoter/enhancer.
  • muscle promoters which are well known in the state of the art and which can be used in the practice of the invention (for a review of specific muscle promoters, see Miller et al., (1993) Bioessays 15: 191-196 ).
  • the agent capable of inducing CT-1 activity is a vector that comprises a polynucleotide as previously defined, i.e. that codes for CT-1 or a functionally equivalent variant thereof.
  • Suitable vectors for the insertion of said polynucleotides are vectors derived from expression vectors in prokaryotes such as pUC18, pUC19, pBluescript and their derivatives, mp18, mp19, pBR322, pMB9, ColE1, pCR1 , RP4, phages and "shuttle" vectors such as pSA3 and pAT28, yeast expression vectors such as vectors of the 2 micron plasmid type, integration plasmids, YEP vectors, centromeric plasmids and such like, expression vectors in insect cells such as the vectors of the pAC series and of the pVL series, expression vectors in plants such as vectors of the pIBI, pEarleyGate, pAV
  • the agent capable of causing an increase in CT-1 activity is a cell capable of secreting cardiotrophin-1 or a functionally equivalent variant thereof into the medium.
  • Suitable cells for the expression of cardiotrophin-1 or of the functionally equivalent variant thereof include, without limitation, cardiomyocytes, adipocytes, endothelial cells, epithelial cells, lymphocytes (B and T cells), mastocytes, eosinophils, cells of the vascular intima, primary culture of cells isolated from different organs, preferably from cells isolated from islets of Langerhans, hepatocytes, leukocytes, including mononuclear, mesenchymal, umbilical cord or adult leukocytes (from the skin, lungs, kidney and liver), osteoclasts, chondrocytes and other connective tissue cells.
  • Established cell lines such as Jurkat t cells, NIH-3T3, CHO, Cos, VERO, BHK, HeLa, COS, MDCK, 293, 3T3 cells, C2
  • Suitable materials for forming the microparticles that are an object of the invention include any biocompatible polymeric material that allows the continuous secretion of therapeutic products, acting as cell support.
  • said biocompatible polymeric material can be, for example, thermoplastic polymers or hydrogel polymers.
  • Thermoplastic polymers include acrylic acid, acrylamide, 2-aminoethyl methacrylate, poly(tetrafluoroethylene-cohexafluoropropylene), methacrylic-(7-cumaroxy) ethyl ester acid, N-isopropyl acrylamide, polyacrylic acid, polyacrylamide, polyamidoamine, poly(amino)-p-xylylene, poly(chloroethyl vinyl ether), polycaprolactone, poly(caprolactone-co-trimethylene carbonate), poly(carbonate urea) urethane, poly(carbonate) urethane, polyethylene, polyethylene copolymer and acrylamide, polyethylene glycol, polyethylene glycol methacrylate, poly(ethylene terephthalate), poly(4-hydroxybutyl acrylate), poly(hydroxyethyl methacrylate), poly(N-2-hydroxypropyl methacrylate), poly(lactic acid-glycolic acid), poly
  • the polymers of hydrogel type include natural materials of alginate, agarose, collagen, starch, hyaluronic acid, bovine serum albumin, cellulose and its derivatives, pectin, chondroitin sulfate, fibrin and fibroin type as well as synthetic hydrogels such as sefarose and sefadex.
  • the microparticle of the invention can be surrounded by a semi-permeable membrane which gives stability to the particles, forming a barrier impermeable to antibodies.
  • Semipermeable membrane means a membrane that allows the entry of all those solutes necessary for cell viability and allows the exit of therapeutic proteins produced by the cells contained in the microparticle, but which is substantially impermeable to antibodies, so that the cells are protected from the immune response produced by the organism housing the microparticle.
  • Suitable materials for forming the semipermeable membrane are materials insoluble in biological fluids, preferably polyamino acids, such as, for example poly-L-lysine, poly-L-ornithine, poly-L-arginine, poly-L-asparagine, poly-L-aspartic, poly benzyl-L-aspartate, poly-S-benzyl-L-cysteine, poly-gamma-benzyl-L-glutamate, poly-S-CBZ-L-cysteine, poly- ⁇ -CBZ-D-lysine, poly- ⁇ -CBZ-DL-ornithine, poly-O-CBZ-L-serine, poly-O-CBZ-D-thyrosine, poly( ⁇ -ethyl-L-glutamate), poly-D-glutamic, polyglycine, poly- ⁇ -N-hexyl L-glutamate, poly-L-histidine, poly( ⁇ ,
  • metabolic disease is understood as all types of disorders that lead to errors and imbalances in the metabolism as well as to metabolic processes taking place in a sub-optimal form.
  • the expression also relates to disorders that can be treated through metabolism modulation, although the disease in itself may not have been caused by a metabolic disorder.
  • the metabolic disease is selected from the set of obesity, hyperglycaemias, insulin resistance, type 2 diabetes, and dyslipemias.
  • the term "obesity”, as used in the present invention, relates to the definition of obesity provided by the WHO based on the body mass index (BMI), which consists of the ratio between the weight of a person (in kg) and the square of their height in metres.
  • BMI body mass index
  • a BMI lower than 18.5 kg/m 2 is considered as insufficient weight or thinness
  • a BMI of 18.5-24.9 kg/m 2 is considered a normal weight
  • a BMI of 25.0-29.9 kg/m 2 is considered grade 1 of overweight
  • a BMI of 30.0-39.0 kg/m 2 is considered a grade 2 of overweight
  • a BMI greater than or equal to 40.0 kg/m 2 is considered morbid obesity.
  • an individual's degree of obesity such as the diameter of the waist measured at the midpoint between the lower limit of the ribs and the upper limit of the pelvis (in cm), the thickness of skin folds, and bioimpedance, based on the principle that a lean mass transmits electricity better than a fatty mass.
  • hyperglycaemia relates to a state where abnormally high blood glucose levels appear in relation to the fasting baseline levels.
  • hyperglycaemia is understood to take place when fasting blood glucose levels are consistently higher than 126 mg/dL, the postprandial glucose levels are higher than 140 mg/dL, and/or the glucose levels in venous plasma 2 hours after administration of a dose of glucose of 1.75 grams for each kilogram of body weight is over 200 mg/dL.
  • insulin resistance relates to a disorder wherein the cells do not respond correctly to insulin. As a result, the body produces more insulin in response to high blood glucose levels. Patients with insulin resistance frequently display high glucose levels and high circulating insulin levels. Insulin resistance is frequently linked to obesity, hypertension, and hyperlipidemia. Additionally, insulin resistance frequently appears in patients with type 2 diabetes.
  • type 2 diabetes relates to a disease characterized by an inappropriate increase in blood glucose levels, which generates chronic complications as it affects large and small vessels and nerves.
  • the underlying disorder in this disease is the difficulty for insulin action (in the form of a loss of tissue sensitivity to this hormone), which is called insulin resistance, and an inadequate secretion of insulin by the cells responsible for their production in the pancreas.
  • insulin resistance in the form of a loss of tissue sensitivity to this hormone
  • insulin resistance an inadequate secretion of insulin by the cells responsible for their production in the pancreas.
  • faulty insulin action frequently translates into an increase in cholesterol and/or triglyceride levels.
  • Dyslipemia relates to any pathological condition characterized by a disorder in the lipid metabolism, with a consequent disorder in lipid concentration (cholesterol, triglycerides and such like) and lipoproteins (high density lipoproteins) in the blood.
  • Dyslipemias that can be treated with the methods of the present invention include, without limitation, hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia of type I, IIa, IIb, III, IV, V, hyperchylomicronemia, combined hyperlipidemia, etc.
  • compositions of the invention are useful both for the treatment of morbid obesity and for the treatment of grade 1 or grade 2 of overweight, in which case the methods of the invention have a cosmetic purpose. Therefore, in another aspect, the invention is related to a cosmetic method for the treatment of obesity which comprises administering to a patient a compound that induces cardiotrophin 1 activity.
  • the patients with excess weight in the form of fat and who can be treated by the cosmetic method of the present invention are identified visually or by having a BMI higher than or equal to 25 kg/m 2 , preferably between 25 and 30. These individuals are considered obese, and needing weight control for cosmetic reasons.
  • the compounds of the invention can be administered both for acute and for chronic treatment.
  • chronic administration as used in the present invention, relates to a method of administration wherein the compound is administered to the patient continuously for extended periods of time in order to maintain the therapeutic form during said period.
  • forms of chronic administration include the administration of multiple doses of the compound daily, twice daily, thrice daily or with more or less frequency.
  • Chronic administration can be carried out by means of different intravenous injections administered periodically throughout a single day.
  • chronic administration involves the administration in the form of bolus or by continuous transfusion which can be carried out daily, every two days, every 3 to 15 days, every 10 days or more.
  • chronic administration is maintained for at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least one year, at least 2 years or more.
  • acute administration relates to a method of administration wherein the patient is exposed to a single dose of the compound or several doses but over a reduced time period, such as, for example, 1, 2, 4, 6, 8, 12 or 24 hours or 2, 3, or 4 days.
  • Therapeutically effective quantity is understood as the quantity of compound that makes it possible to totally or partially alleviate the symptoms associated with a metabolic disease or which prevents the progression or worsening the symptoms or which prevents the appearance of the disease in a subject at risk from suffering the disease.
  • chronic administration of the compound of the invention can be administered in a sustained release composition such as that disclosed in documents US5672659 , US5595760 , US5821221 , US5916883 and WO9938536 . Otherwise, if acute administration is desired, a treatment with immediate release will be preferred. Irrespective of the type of administration, the quantity of the dose and the interval can be individually adjusted to provide plasma levels of the compounds sufficient for maintaining the therapeutic effect. Someone with normal experience in the state of the art will be capable of optimizing the therapeutically effective local doses without too much experimentation.
  • compositions in the practice of the method of the invention include a therapeutically effective quantity of an active agent, and pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal government or of a state or included in the USA Pharmacopoeia or another generally recognized pharmacopoeia, for use in animals, and more particularly in humans.
  • carrier relates to a diluent, coadjuvent, excipient, or vehicle whereby the therapeutic compound is administered.
  • Said pharmaceutical carriers can be sterile liquids, such as water and oils, including petroleum, animal or plant origin or synthetic oils, such a peanut oil, soy oil, mineral oil, sesame oil and such like.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, powdered skimmed milk, glycerol, propylene glycol, water, ethanol and such like.
  • the composition if desired, can also contain smaller quantities of wetting or emulsifying agents, or pH buffering agents.
  • compositions may take the form of solutions, suspensions, tablets, pills, capsules, powder, prolonged release formulations and such like.
  • the composition may be formulated as a suppository, with binders and traditional carriers such as triglycerides.
  • the oral formulation can include standard carriers such as pharmaceutical types of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • the composition can be formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, or intramuscular administration to human beings.
  • the composition may also include a solubilising agent and a local anaesthetic such as lidocaine to relieve pain at the injection site.
  • a solubilising agent such as lidocaine to relieve pain at the injection site.
  • a local anaesthetic such as lidocaine to relieve pain at the injection site.
  • the composition When the composition is going to be administered by infiltration, it can be dispensed with an infiltration bottle which contains water or saline solution of pharmaceutical quality.
  • a water vial can be provided for injection or sterile saline solution, so that the ingredients can be mixed before administration.
  • the quantity of CT-1 activity inducing compound that will be effective in the treatment of metabolic disease can be determined by standard clinical techniques based on the present description. Furthermore, in vitro tests can also be optionally used to help identify optimum dosage ranges.
  • the precise dose to use in the formulation will depend on the administration route, and the severity of the condition, and it should be decided at the doctor's judgement and depending on each patient's circumstances.
  • the dosage ranges suitable for intravenous administration are generally 50-5000 micrograms of active compound per kilogram of body weight.
  • the dosage ranges suitable for intranasal administration are generally approximately of 0.01 pg/kg of body weight to 1 mg/kg of body weight.
  • the effective doses can be extrapolated from a pair of response curves to doses derived from model in vitro assay systems or in animals.
  • a therapeutically effective dose can be initially estimated from in vitro assays.
  • a dose can be formulated in animal models to achieve a circulating concentration range which includes the IC50 which has been determined in cell culture. Said information can be used to precisely determine useful doses in humans.
  • the initial doses can also be estimated from in vivo data, e.g. animal models, using techniques well known in the state of the art. Someone with normal experience in the state of the art can easily optimize administration to humans based on the data in animals.
  • the invention envisages the combined use of the agent capable of inducing CT-1 activity with one or several compounds capable of reducing the availability of nutrients in the organism, which have an anorexigenic effect or which have an anti-obesity effect.
  • the metabolic disease treatment methods in accordance with the invention envisage the joint, sequential or separate administration of the compounds with capacity for inducing CT-1 activity with one or several compounds selected from the group of amylin, amylin agonists, calcitonin salmon, cholecystokinin or an agonist thereof, leptin (OB protein), exendin or an exendin analog, GLP1 or an agonist thereof, polypeptides (PYY) or agonists thereof, agents that affect neurotransmitters or neuronal ion channels such as anti-depressants, noradrenaline capture inhibitors, serotinin 2c receptor agonists, some dopaminergic antagonists, cannabinoid 1 receptor agonists, agents which modulate the route of leptin/insulin
  • compositions of the invention are provided.
  • figure 7 shows how the treatment of mice subjected to the experimental destruction of beta pancreatic cells with streptozotocin with a combination of CT-1 and insulin results in a hypoglycaemic effect higher than that observed after administration of each one of the components separately.
  • figure 8 shows how the combination of CT-1 and insulin causes an increase in glucose capture by muscles higher than that observed with any of the compounds administered separately.
  • the invention is related to a composition (hereinafter, composition of the invention) which comprises, together or separately, a compound that induces cardiotrophin activity and an anti-diabetic compound.
  • anti-diabetic compound is understood as an agent which, irrespective of its action mechanism, is capable of at least partially compensating for the symptoms of diabetes, including hyperglycaemia.
  • the anti-diabetic compound is a compound that induces insulin activity or a compound that induces hypoglycaemic activity of insulin or sensitizing agent to insulin activity.
  • the anti-diabetic compounds capable of inducing insulin activity include, without limitation,
  • insulin as used in the present invention, relates to insulin of any species (primate, rodent or rabbit), but preferably of human origin and more preferably insulin of native sequence, which comprises a polypeptide which has the same sequence of amino acids as the insulin derived from nature. Said insulin polypeptides of native sequence can be isolated from nature or can be produced by recombinant and/or synthetic medium.
  • native sequence insulin specifically covers the truncated or secreted forms and allelic variants that occur naturally.
  • the native sequence human insulin is a mature native sequence insulin or of a complete length which comprises an alpha or A chain, corresponding to amino acids 90 to 110 of the sequence of human preproinsulin (access number P01308 in the UniProtKB database in version 126 with date 20.01.2009) and a beta or B chain, corresponding to amino acids 25 to 54 (access number P01308 in the NCBI database in version 126 with date 20.01.2009).
  • “Functionally equivalent variant of insulin” is understood as all those polypeptides resulting from the elimination, insertion or modification of at least one amino acid with respect to the insulin sequence and which substantially maintains the same properties as the insulin it comes from. Insulin activity can be determined by methods widely known by those skilled in the art such as normoglycaemic clamping or the measurement of glycosylated proteins in serum ( Bunn et al., Diabetes, 1981, 30:613-617 ).
  • Functionally equivalent variants of insulin include, without limitation, the des-pentapeptide (B26-B30)-Phe B21 - ⁇ -carboxamide]insulin, Asp B10 insulin (disclosed in US4992417 ), Lys B28 -Pro B29 insulin Lys B28 -Pro B29 and the hexameric variant thereof (disclosed in US5474978 and US5514646 ), formulations of insulin and protamine ( US5650486 ), acylated Lys B28 -Pro B29 insulin ( US5922675 ), and compositions of stabilized insulin such as those disclosed in US5952297 , US6034054 and US6211144 , superactive analogs of insulin, monomeric insulins, hepatospecific insulins, insulin lispro (Humalog®), insulin lispro formulated with insulin lispro protamine (marketed as Humalog ®50/50 TM , Humalog® 75/25 TM ), NPH insulin or insulin isophan
  • functionally equivalent variants of insulin include polypeptides that show at least approximately 80% of identity of amino acid sequence with the sequence of amino acids of: (a) residues 1 to 21 of the high-fat diet A chain in combination with residues 1 to 30 of the high-fat diet B chain, or (b) another fragment specifically derived from said sequences.
  • the secondary structure of the insulin maintained by disulfide bonds between cysteine residues A6-Al1, A7-B7 and A20-B 19 seems necessary for the activity, for which reason the functionally equivalent variants preferably preserve said secondary structure as much as possible.
  • Functionally equivalent variants of insulin include, for example, the polypeptides wherein one or more amino acid residues are added, or deleted, at the N- and/or C-terminal ends, as well as within one or more of the internal domains, of the A and B chains of insulin.
  • a polypeptide variant of insulin will have at least approximately an identity of amino acids sequence with the sequence formed by residues 1 to 21 of the A chain of the high-fat diet in combination with residues 1 to 30 of the B chain of the high-fat diet or with another fragment specifically derived from said sequences of amino acids of at least 80%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of identity of amino acids sequence.
  • polypeptide variants will have a sequence length of at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 of the A chain and at least 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 27, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 residues of the B chain.
  • Polynucleotides which code for insulin include both the polynucleotide that codes for human insulin as well as the precursors thereof (preproinsulin and proinsulin), as well as the orthologs of other species.
  • Polynucleotide that codes for a functionally equivalent variant of insulin indicates (a) a nucleic acid that codes for a polypeptide of active insulin as defined above, and which has at least approximately 80% identity of nucleic acid sequence with a nucleic acid sequence that codes for: (a) residues 1 to 21 of the A chain of the high-fat diet defined above in combination with residues 1 to 30 of the B chain of the human insulin polypeptide defined above, or (b) one of nucleic acid that codes for another fragment specifically derived from the aforementioned sequences of amino acids which shows at least 80%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of identity of amino acid sequence with said sequences.
  • the polynucleotides which code for a variant of insulin contain a nucleic acid that codes for an A chain of insulin of at least approximately 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 81, 87, 105 nucleotides and/or a nucleic acid that codes for a B chain of insulin of at least approximately 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129, 132, 135 or 150 nucleotides.
  • Said polynucleotides may appear isolated or be found as part of a vector.
  • Suitable vectors for the expression of the polynucleotides that code for insulin or the functionally equivalent variant thereof are essentially the same as those previously described in relation to the composition comprised by CT-1.
  • the anti-diabetic compounds that can be used in the context of the present invention include compounds which that antiglycaemic activity of the insulin or sensitizing agents of insulin activity and include, without limitation, secretagogues of insulin such as the sulfonylureas (tolbutamide, chlorpropamide, glipicide, glibenclamide, glicazide, glipentide, glimepiride, glibenclamide, glipizide, gliquidone, glisentide, glimepride and such like) and metiglinides (repaglinide, nateglinide, mitiglinide and such like), reducing agents of liver glucose production (biguanides and, in particular, metformin and buformin), agents which cause carbohydrate decrease such as ⁇ -glucosidase inhibitors (acarbose, miglitol or voglibose), agents that increase peripheral use of glucose such as thiazolidinediones (rosi)
  • compositions of the invention can be used for the treatment of metabolic disease given their hypoglycaemic effects and their capacity to increase glucose capture by muscles (see example 2).
  • Said compositions can be used as preparations of the different compounds for their administration simultaneously, separately or sequentially.
  • the invention is related to a composition of the invention for the treatment of a metabolic disease wherein the composition is administered simultaneously, separately or sequentially.
  • the invention is related to the use of a composition of the invention for the preparation of a drug for the treatment of a metabolic disease wherein the composition is administered simultaneously, separately or sequentially.
  • the invention is related to a method for the treatment of a metabolic disease which comprises the simultaneous, separate or sequential administration of a composition of the invention.
  • compositions of the invention in particular, the CT-1 activity inducer agent and the anti-diabetic agent, can be presented as a single formulation (for example, as a tablet or a capsule comprising a fixed quantity of each one of the components) or can, on the other hand, be presented as separate formulations to be later combined for joint, sequential, or separate administration.
  • compositions of the invention also include the formulation as a kit-of-parts wherein the components are formulated separately but are packaged in the same container.
  • the formulation of the first and second components of the compositions of the invention may be similar, in other words, similarly formulated (in tablets or pills), which allows their administration by the same route.
  • the two components can be presented in a blister.
  • Each blister contains the drugs that must be consumed during the day. If the drugs must be administered several times a day, the drugs corresponding to each administration can be placed in different sections of the blister, preferably recording in each section of the blister the time of day when they should be administered.
  • the components of the composition of the invention can be formulated differently so that the different components are differently administered.
  • the first component is formulated as a tablet or capsule for its oral administration and the second component is formulated for its intravenous administration.
  • compositions of the invention are administered by the methods known to those skilled in the art, including, but without limitation, intravenous, oral, nasal, parenteral, topical, transdermal, rectal, and such like.
  • the ratio between the components that are part of the compositions of the invention shall depend on the CT-1 activity inducer agent and the anti-diabetic agent used in each particular case, as well as of the desired indication.
  • the invention envisages compositions wherein the ratio between the quantities of the two components can range from 50:1 to 1:50, in particular from 20:1 to 1:20, from 1:10 to 10:1, or from 5:1 to 1:5.
  • the metabolic diseases that can be treated with the compositions of the invention include, without limitation, obesity, insulin resistance, hyperglycaemia, dyslipemia, and type 2 diabetes, as has been previously described in relation to the first aspect of the invention (therapeutic and cosmetic uses of CT-1).
  • the invention is related to a cosmetic method for the treatment of obesity which comprises administering a patient a composition in accordance with the invention, wherein those patients candidate to an anti-obesity treatment for purely cosmetic reasons are identified as has been described in the first aspect of the invention (therapeutic and cosmetic uses of CT-1).
  • Obese mice were obtained by the intake of a high-fat diet (HFD, 60% fat) during 3 months.
  • HFD high-fat diet
  • the intravenous administration for 6 consecutive days of rCT-1 caused a reduction in the body weight of C57BL/6 mice (5 months of age) with high-fat diet (HFD) ( Fig. 1 ).
  • the dose used in this experiment did not produce a feverish reaction (rectal temperature was measured during all days of treatment).
  • the figure shows the kilocalories ingested during the 6 days of treatment of the group treated with rCT-1 and its corresponding control group treated with physiological serum intravenously (S).
  • rCT-1 0.2mg/kg/day
  • NCD normal diet
  • the first group received a physiological serum intravenously (the same volume as that used for the administration of rCT-1); the second group (rCT-1 group) received rCT-1 intravenously at the aforementioned dose (0.2mg/kg/day) and the third group (Pair-Fed group) received the same quantity of food daily as that ingested by the mice treated with rCT-1 and which were injected with serum during the same experimental period.
  • mice treated with rCT-1 lost more weight than the pair-fed group, despite the energy intake being identical in both groups, indicating that in addition to the previously observed anorexigenic effect, rCT-1 would have other metabolic effects responsible for weight loss.
  • mice C57BL/6, 3 months of age
  • gastric gavage in a volume 1% body weight
  • the intravenous administration of the same volume of saline serum was given (Saline) or rCT-1 (10 ⁇ g). Blood was taken at the hours indicated in the graphic and blood sugar was measured observing that no increase in blood sugar occurred in the animals treated with rCT-1 ( Fig. 6 ).
  • mice C57BL/6, 3 months of age
  • streptozotocin 200mg/kg
  • the first group (saline group) was treated with treated with saline serum; the second group (Insulin group) was treated with 0.75U/kg insulin, the third group (rCT-1 group) was treated with 10 ⁇ g of rCT-1 and the fourth group (Insulin group + rCT-1) was treated with 0.75U/kg of insulin and 10 ⁇ g of rCT-1.
  • the different treatments have been administered, blood sugar was measured after 15, 30, 60 and 120 min. As observed in figure 7 , rCT-1 significantly decreased blood sugar 30 min after its administration and enhanced the effects of insulin in all blood extraction points analysed.
  • mice In order to determine if the hypoglycaemic effect resulting from acute treatment with rCT-1 is due to an increase in glucose capture by muscles, muscular capture of 18FDG (18 FluoroDeoxyGlucose) was determined by gamma counter in different groups of mice. To perform this experiment, the mice (C57BL/6, 3 months of age) were divided into 4 groups as follows: Saline group (treated with saline serum); Insulin group (treated with 0.75U/kg insulin), rCT-1 group (treated with 10 ⁇ g of rCT-1) and Insulin group + rCT-1 (treated with 0.75U/kg of insulin + 10 ⁇ g of rCT-1.
  • rCT-1 may increase glucose consumption by muscles and enhance (although not significantly with respect to those observed with insulin).
  • hypoglycaemic and hypoinsulinemic effects of chronic treatment with rCT-1 were determined in C57BL/6 mice (5 months of age) with obesity induced by the intake of a high-fat diet (HFD, 60% fat) for 3 months.
  • HFD high-fat diet
  • the mice were treated for 6 consecutive days (chronic treatment) with rCT-1 (0.2mg/kg/day) administered endovenously.
  • rCT-1 0.2mg/kg/day
  • the hypoglycaemic and hypoinsulinemic effects of chronic treatment with rCT-1 were compared with their corresponding pair-fed (PF) group.
  • the rCT-1 group received rCT-1 by intravenous route at the aforementioned dose (0.2mg/kg/day) for 6 days; the Pair-Fed group received the same quantity of daily food as that ingested by the mice treated with rCT-1 and serum was injected into them for the same experimental period.
  • the intestinal transport of glucose was determined by measuring the capture of ⁇ -methylglucoside (1 mM) by everted jejunum rings for 15 minutes of incubation in the absence or presence of r-CT-1 at 37° C.
  • the ⁇ -methylglucoside is an analog of the glucose which only crosses the apical membrane of the enterocyte by the SGLT1 sodium-sugar co-transcarrier, which means that the changes in their transport should be attributed to changes in the activity of said transcarrier.
  • Figure 11 shows that CT-1 is capable of inhibiting the absorption of glucose in the intestine although the effect observed is not dose-dependent.
  • Figure 16 shows the results of an experiment carried out on primary cultures of rat adipocytes to determine the capacity of rCT-1 and CNTF to modulate leptin secretion by adipocytes.
  • Figure 16A shows how treatment with rCT-1 (72 h) inhibits both baseline secretion of leptin and that stimulated by insulin (1.6 nM). However, these effects were not observed with similar concentrations of CNTF ( figure 16B ).
  • Figure 17 shows the results of experiments made in primary cultures of rat adipocytes to determine the ability of CT-1 and CNTF to modulate lipolysis in the absence or presence of insulin.
  • CT-1 is able to induce the release of glycerol (lipolysis measurement) and also inhibits the anti-lipolytic activity of insulin, however CNTF is not able.
  • CT-1 is able to induce typical genes of brown adipose tissue in adipocytes (deiodinase iodothyronine type II, Dio-2 and uncoupling protein-1, UCP-1) while CNTF is not able ( figure 18 ).
  • adipocytes deiodinase iodothyronine type II, Dio-2 and uncoupling protein-1, UCP-1
  • CNTF uncoupling protein-1
  • histological cuts of liver were performed in order to detect by microscopy the appearance of symptoms of inflammation.
  • the results show images representative of histological cuts of liver (H&E 100X) in 3 groups of mice (C57BL/6, 4 months of age): Control group: which received physiological serum by intravenous route (the same volume as that used for the administration of rCT-1); rCT-1 group: which received rCT-1 by intravenous route at the aforementioned dose (0.2mg/kg/day) for 6 consecutive days; Pair-Fed group: which received the same quantity of daily food as that the mice treated with rCT-1 would ingest and into which serum was injected during the same experimental period.
  • Control group which received physiological serum by intravenous route (the same volume as that used for the administration of rCT-1)
  • rCT-1 group which received rCT-1 by intravenous route at the aforementioned dose (0.2mg/kg/day) for 6 consecutive days
  • Pair-Fed group which received the same quantity of daily food as that the mice
  • rCT-1 accelerated the elimination of free fatty acids in serum after an intralipid injection.
  • the control animals received saline.
  • the concentration of free fatty acids in serum was determined after 5 minutes.
  • the elimination values of the free fatty acids taken at different times were normalized with respect to the FFA values 5 minutes after the injection of intralipids (100%).
  • the abulia kinetics of the FFA significantly differered between the mice treated with saline and with CT-1 ( P ⁇ 0.05 by two-way ANOVA with Bonferroni analysis post hoc ).
  • Skeletal muscle is the most sensitive tissue to insulin action and provides in healthy individuals for 90% of glucose uptake stimulated by insulin.
  • CT-1 enhances insulin signaling in muscle " in vitro " and "in vivo ".

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US10405961B2 (en) 2013-03-14 2019-09-10 Cell and Molecular Tissue Engineering, LLC Coated surgical mesh, and corresponding systems and methods
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Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL68769A (en) 1983-05-23 1986-02-28 Hadassah Med Org Pharmaceutical compositions containing insulin for oral administration
US4849405A (en) 1984-05-09 1989-07-18 Synthetic Blood Corporation Oral insulin and a method of making the same
EP0179904A1 (en) 1984-05-09 1986-05-07 Medaphore Inc. Oral insulin and a method of making the same
US4963526A (en) 1984-05-09 1990-10-16 Synthetic Blood Corporation Oral insulin and a method of making the same
US5614492A (en) 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US4992417A (en) 1987-07-17 1991-02-12 Mount Sinai School Of Medicine Superactive human insulin analogues
US5514646A (en) 1989-02-09 1996-05-07 Chance; Ronald E. Insulin analogs modified at position 29 of the B chain
US5642868A (en) 1990-05-02 1997-07-01 The United States Of America As Represented By The Secretary Of The Navy Ceramic material
IL99699A (en) 1990-10-10 2002-04-21 Autoimmune Inc Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes
US5672659A (en) 1993-01-06 1997-09-30 Kinerton Limited Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
US6191105B1 (en) 1993-05-10 2001-02-20 Protein Delivery, Inc. Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
US5474978A (en) 1994-06-16 1995-12-12 Eli Lilly And Company Insulin analog formulations
US5461031A (en) 1994-06-16 1995-10-24 Eli Lilly And Company Monomeric insulin analog formulations
US5595760A (en) 1994-09-02 1997-01-21 Delab Sustained release of peptides from pharmaceutical compositions
US5547929A (en) 1994-09-12 1996-08-20 Eli Lilly And Company Insulin analog formulations
US5693609A (en) 1994-11-17 1997-12-02 Eli Lilly And Company Acylated insulin analogs
US5843866A (en) 1994-12-30 1998-12-01 Hampshire Chemical Corp. Pesticidal compositions comprising solutions of polyurea and/or polyurethane
YU18596A (sh) 1995-03-31 1998-07-10 Eli Lilly And Company Analogne formulacije monomernog insulina
US5824638A (en) 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
US5665702A (en) 1995-06-06 1997-09-09 Biomeasure Incorporated Ionic molecular conjugates of N-acylated derivatives of poly(2-amino-2-deoxy-D-glucose) and polypeptides
US5916883A (en) 1996-11-01 1999-06-29 Poly-Med, Inc. Acylated cyclodextrin derivatives
US6153632A (en) 1997-02-24 2000-11-28 Rieveley; Robert B. Method and composition for the treatment of diabetes
CO4750643A1 (es) 1997-06-13 1999-03-31 Lilly Co Eli Formulacion estable de la insulina que contiene l-arginina y protamina
DE69916031T2 (de) 1998-01-29 2005-02-17 Poly-Med Inc. Asorbierbare mikropartikel
ATE251465T1 (de) 1998-07-31 2003-10-15 Novo Nordisk As In-vitro stimulation von beta zellen vermehrung
US6211144B1 (en) 1998-10-16 2001-04-03 Novo Nordisk A/S Stable concentrated insulin preparations for pulmonary delivery
CA2494040A1 (en) * 2002-07-29 2004-02-05 Es Cell International Pte Ltd. Multi-step method for the differentiation of insulin positive, glucose
WO2005053728A2 (de) * 2003-12-01 2005-06-16 Xantos Biomedicine Ag Mit adipositas assoziierte proteine und deren verwendung in therapie und diagnostik
GT200600046A (es) * 2005-02-09 2006-09-25 Terapia de combinacion
WO2006097526A1 (en) * 2005-03-17 2006-09-21 Novo Nordisk A/S Compounds for use in the treatment of obesity
TW200800920A (en) 2006-02-15 2008-01-01 Sanofi Aventis Novel azacyclyl-substituted arylthienopyrimidinones, process for their preparation and their use as medicaments

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HONGKUI J ET AL: "In vivo effects of cardiotrophin-1", CYTOKINE, ACADEMIC PRESS LTD, PHILADELPHIA, PA, US, vol. 8, no. 12, 1 December 1996 (1996-12-01), pages 920 - 926, XP002966035, ISSN: 1043-4666, DOI: 10.1006/CYTO.1996.0123 *
NATAL CRISTINA ET AL: "Cardiotrophin-1 is expressed in adipose tissue and upregulated in the metabolic syndrome.", January 2008, AMERICAN JOURNAL OF PHYSIOLOGY. ENDOCRINOLOGY AND METABOLISM JAN 2008 LNKD- PUBMED:17940213, VOL. 294, NR. 1, PAGE(S) E52 - E60, ISSN: 0193-1849 *
PATEL SANJEEV B ET AL: "Leptin: linking obesity, the metabolic syndrome, and cardiovascular disease.", April 2008, CURRENT HYPERTENSION REPORTS APR 2008 LNKD- PUBMED:18474180, VOL. 10, NR. 2, PAGE(S) 131 - 137, ISSN: 1534-3111 *
WHITE URSULA A ET AL: "Neuropoietin attenuates adipogenesis and induces insulin resistance in adipocytes.", 15 August 2008, THE JOURNAL OF BIOLOGICAL CHEMISTRY 15 AUG 2008 LNKD- PUBMED:18562323, VOL. 283, NR. 33, PAGE(S) 22505 - 22512, ISSN: 0021-9258 *

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